Schizophrenia is frequently characterized by a disabling and lifelong course of illness, making it imperative that interventions to alter its deleterious effects be applied as early as possible. Cognitive impairments are among the most disabling aspects of the illness, and represent critical targets for early intervention. Our earlier studies have shown that cognitive rehabilitation approaches designed to capitalize on existing brain resources and enhanced neuroplasticity demonstrate significant promise for improving cognition and functional outcome in early course schizophrenia. These beneficial effects of cognitive rehabilitation presumably reflect alterations in the structural and functional integrity of the brain. We have observed exciting preliminary evidence from our recently completed early course trial of Cognitive Enhancement Therapy (CET) indicating that the early application of this novel neurocognitive and social-cognitive rehabilitation approach can prevent fronto-temporal gray matter loss in early course schizophrenia. Beyond our preliminary observations, however, remarkably little is known about the effects of cognitive rehabilitation on diverse functional and structural brain parameters early in the disorder. The capacity of the schizophrenia brain to respond to non-pharmacologic intervention is of substantial significance, and identifying the effects of cognitive rehabilitation on the brain in early course schizophrenia is critical for elucidating the neurobiologic mechanisms of action of these approaches, clarifying the requisite brain changes that can support cognitive enhancement, and refining current treatments. This project proposes to study the effects of CET on brain function and structure in early course schizophrenia. Patients in the early course of the disorder (illness duration < 5 years) will be randomly assigned to CET (N = 51) or an Enriched Supportive Therapy (EST) control (N = 51) and treated for 18 months. Assessments of brain function and structural integrity prior to treatment, at 9 and 18 months will be conducted using magnetic resonance imaging to examine the differential effects of CET on fronto-temporal brain regions previously implicated in neurocognitive and social-cognitive impairments in schizophrenia. In addition, comprehensive data on cognition and functional outcome will be collected to examine the degree to which cognitive and functional improvement during CET is mediated by neurobiologic change. Neuroimaging, cognitive, and functional assessments will also be completed at 1-year post-treatment to examine the durability of CET effects on the brain, cognition, and behavior. Finally, moderator analyses will explore whether a greater pre-treatment neurobiologic reserve is predictive of treatment response, thus allowing the possible personalization of care. Together, this project will result in the first comprehensive characterization of the neurobiologic effects of cognitive rehabilitation in early course schizophrenia, and provide critical information on the neural mechanisms, predictors and durability that are needed to refine and extend current approaches to optimize therapeutic outcomes for early course schizophrenia patients. PUBLIC HEALTH RELEVANCE: This proposed project would be the first comprehensive study of the effects of cognitive rehabilitation on brain structure and function in early course schizophrenia. The information gathered from the project is of significant public health relevance, in that it will characterize the capacity of the schizophrenia brain to respond to non-drug cognitive intervention, point to the requisite neural changes and pre-treatment brain resources that can support cognitive and functional improvement in the early phase of the disorder, and identify the degree to which brain benefits can be maintained after the completion of treatment. Such information is vital for refining and extending existing approaches, personalizing care, and developing new interventions to successfully alter the greatly disabling course of schizophrenia.